We have examined the possibility that daily blood pressure rhythms are produced by variation in activation of the sympathetic nervous system by studying circadian rhythms of blood pressure in mice with a deficiency in beta1 and beta2 adrenergic receptors, the two receptors primarily involved in the control of cardiovascular function. Our data show, surprisingly, that blood pressure rhythmicity is virtually unaltered in beta1beta2-adrenergic receptor-deficient mice although mean arterial pressure was significantly reduced. beta1beta2-deficiency is associated with significantly reduced levels of spontaneous activity, an independent determinant of blood pressure. However, even when the effect of activity was eliminated by analyzing only those measurements without any activity, 24 hour variations of blood pressure persisted and they were not different between wild type and mutant mice. Thus, beta-adrenergic receptors are not required for hypothalamic clock genes to drive a robust blood pressure rhythm.[unreadable] [unreadable] Since nitric oxide is a powerful vasodilator it seemed conceivable that diurnal variations in the generation of NO may be responsible for the 24 hour blood pressure rhythm. We tested this possibility by comparing blood pressure rhythms in wild type mice with those in mice deficient in neuronal nitric oxide synthase (NOS) or endothelial NOS or in both neuronal and endothelial NOS. Our data show robust blood pressure rhythms in the absence of neuronal or endothelial NOS although the level of blood pressure was elevated in the absence of endothelial NOS. Thus, variations in NO generation are not responsible for blood pressure variability. The vascular abnormalities observed in mice with NKCC1 deficiency prompted us to investigate the blood pressure rhythmicity in NKCC1 deficient mice. Blood pressures were found to be normal and cycle with a normal amplitude in the absence of NKCC1 in mice fed a standard diet. However, NKCC1-- mice had increased blood pressures when supplied with a high NaCl diet without an effect on blood pressure rhythms. [unreadable] [unreadable] The islet antigen IA-2 is expressed in the suprachiasmatic nucleus where an interplay between a number of different so-called clock genes generates the cycle of gene expression changes that underlie the biological rhythms. We have performed studies of 24 h variations of blood pressure, core body temperature, and locomotor activity in IA2IA-2beta-deficient mice, two related proteins expressed in dense core vesicles that have been recognized as major autoantigens in diabetes mellitus. In these studies we have observed that 24 hour rhythms of blood pressure, body temperature, and spontaneous and wheel running activity is completely absent in the mutant mice. This is due to a total absence of the increase in blood pressure, temperature, and activity that normally occurs in the night time. Absence of circadian rhythms persisted when the external cue of daylight was removed. There was no general defect in cardiac function since mutant mice were able to respond to a stressor (cage change stress) with a normal increase in blood pressure and heart rate. Furthermore, IA-2IA-2beta-deficient mice are largely normal in a number of behavioral tests. The disturbance in circadian blood pressure and activity rhythmicity in these mice is unique since it is evident in the presence of a 12 h lightdark cycle while in most instances rhythm disturbances become only evident under free running conditions, i.e. without the external light cue.